Abstract:

Despite the efficacy of most cancer therapies, drug resistance remains a major problem in the clinic.
The eradication of the entire tumor and the cure of the patient by chemotherapy alone are rare, in particular for
advanced disease. From an evolutionary perspective, the selective pressure exerted by chemotherapy leads to the
emergence of resistant clones where resistance can be associated with many different functional mechanisms at
the single cell level or can involve changes in the tumor micro-environment. In the last decade, tumor genomics
has contributed to the improvement of our understanding of tumorigenesis and has led to the identification of
numerous cellular targets for the development of novel therapies. However, since tumors are by nature extremely
heterogeneous, the drug efficacy and economical sustainability of this approach is now debatable. Importantly,
tumor cell heterogeneity depends not only on genetic modifications but also on non-genetic processes involving
either stochastic events or epigenetic modifications making genetic biomarkers of uncertain utility. In this review,
we wish to highlight how evolutionary biology can impact our understanding of carcinogenesis and resistance to
therapies. We will discuss new approaches based on applied ecology and evolution dynamics that can be used to
convert the cancer into a chronic disease where the drugs would control tumor growth. Finally, we will discuss
the way metabolic dysfunction or phenotypic changes can help developing new delivery systems or phenotypetargeted
drugs and how exploring new sources of active compounds can conduct to the development of drugs
with original mechanisms of action.

Abstract:Despite the efficacy of most cancer therapies, drug resistance remains a major problem in the clinic.
The eradication of the entire tumor and the cure of the patient by chemotherapy alone are rare, in particular for
advanced disease. From an evolutionary perspective, the selective pressure exerted by chemotherapy leads to the
emergence of resistant clones where resistance can be associated with many different functional mechanisms at
the single cell level or can involve changes in the tumor micro-environment. In the last decade, tumor genomics
has contributed to the improvement of our understanding of tumorigenesis and has led to the identification of
numerous cellular targets for the development of novel therapies. However, since tumors are by nature extremely
heterogeneous, the drug efficacy and economical sustainability of this approach is now debatable. Importantly,
tumor cell heterogeneity depends not only on genetic modifications but also on non-genetic processes involving
either stochastic events or epigenetic modifications making genetic biomarkers of uncertain utility. In this review,
we wish to highlight how evolutionary biology can impact our understanding of carcinogenesis and resistance to
therapies. We will discuss new approaches based on applied ecology and evolution dynamics that can be used to
convert the cancer into a chronic disease where the drugs would control tumor growth. Finally, we will discuss
the way metabolic dysfunction or phenotypic changes can help developing new delivery systems or phenotypetargeted
drugs and how exploring new sources of active compounds can conduct to the development of drugs
with original mechanisms of action.